The formation of post-surgical adhesions involving organs of the peritoneal cavity and the peritoneal wall is a frequent and undesirable result of abdominal surgery. Surgical trauma to the tissue caused by handling and drying results in release of a serosanguinous (proteinaceous) exudate that tends to collect in the pelvic cavity. If the exudate is not absorbed or lysed within a short time following the surgery, it becomes ingrown with fibroblasts. Subsequent collagen deposition leads to adhesion formation.
Numerous previously known methods have been developed to attempt to eliminate adhesion formation, but with limited success. Such methods include lavage of the peritoneal cavity, administration of pharmacological agents, and the application of barriers to mechanically separate tissues. For example, Boyers et al., “Reduction of postoperative pelvic adhesions in the rabbit with Gore-Tex surgical membrane,” Fertil. Steril., 49:1066 (1988), describes the use GORE-TEX® (a registered trademark of W.L. Gore & Assocs., Inc., Newark, Del.), expanded PTFE surgical membranes to prevent adhesions. Holtz, “Prevention and management of peritoneal adhesions,” Fertil. Steril., 41:497–507 (1984) provides a general review of adhesion prevention. None of the methods described in those articles has been cost effective and efficacious in in vivo studies.
Most adhesion prevention strategies have focused on either pharmacological approaches or barrier approaches. Pharmacological approaches have mainly relied on the local instillation of drugs such as antiinflammatory or fibrinolytic compounds. The advantage of the pharmacological approach is that the drugs can have not only a local but also a regional effect. The regional effect is particularly useful because, although iatrogenic injury is associated with adhesion formation, it is often difficult to predict all of the sites that may have been traumatized or exposed to ischemia during surgery. For example, during open surgical procedures, tissue often may be subjected to long periods of desiccation and surgical handling.
The word “local” as used herein is meant to connote a specific site on a tissue or organ surface, which for example is felt to be at risk for adhesion formation. The term “regional” as used herein, is meant to connote the general cavity or space within which any of several organs are at risk for adhesion formation, but where it is for example, difficult to predict all the sites where such adhesions may form.
Instillation of drugs in regional spaces, such as the peritoneal cavity, has been widely adopted for the prevention of post-surgical adhesions. Unfortunately, most drugs administered in this fashion have a limited residence time at the site of instillation and are rapidly cleared. Also, delivery problems attributable to ischemia may reduce the effectiveness of the drugs. In addition, adhesions may develop not only due to surgical insults, but also due to a variety of pathologies and etiologies that may not be addressed using a pharmacological approach.
In view of the foregoing, it would be desirable to provide methods of preventing post-surgical tissue adhesion that overcome the drawbacks of previously known methods while providing the regional benefits obtained from pharmacological approaches.
Previously known barrier methods rely on the ability to interpose an inert or absorbable material in between organs at risk of formation of adhesions. A variety of materials have been used as barriers, including pentapeptides or elastin, trypsin treated gamma-irradiated amniotic membranes, polyesterurethane-polydimethylsiloxane, carboxymethylcellulose sponge, collagen etc. These previously known materials, however, have been used primarily in academic contexts and have not been developed as commercial products.
Commercially available local barriers, such as sold under the name INTERCEED™, a registered trademark of Johnson and Johnson, Inc., New Brunswick, N.J., SEPRAFILM™, Genzyme Corp., Cambridge, Mass. and REPEL™ under development by Life Medical Corp., Edison, N.J., rely on interposing a barrier material that is absorbed within a 28 day period to reduce adhesion formation. These barriers, however, may have limited efficacy due to migration of the barriers from a local implantation site. Moreover, these barriers do not provide the regional effect observed with pharmacological barriers.
Barriers that may be applied as a liquid also have been used, such as hyaluronic acid based products such as SEPRACOAT™, marketed by Genzyme Corp., Cambridge, Mass. U.S. Pat. No. 5,140,016 to Goldberg et al. describes a method and composition for preventing surgical adhesions using a dilute solution of a hydrophilic polymer such as hyaluronic acid. U.S. Pat. No. 5,190,759 to Lindblad et al. describes a composition and method for prevention of adhesions using solutions containing dextran and hyaluronic acid. These liquid barriers are rapidly cleared from a body cavity after instillation and thus may not be effective in preventing adhesions. Instead, such compositions are more effective as tissue protecting solutions during surgery rather than for the prevention of post-surgical adhesions.
Previously known attempts to prolong the residence of flowable barriers have attempted to form lightly crosslinked liquid barriers that still retain their flow characteristics. Thus, for example, LUBRICOAT™, available from Lifecore Biomedical Inc., Chaska, Minn., is a ferric hyaluronate crosslinked slurry considered for adhesion prevention. This material has been found to have only limited efficacy, however, because the barrier tends to migrate from the application site. Thus, tissues that naturally appose each other still form adhesions.
Other natural and synthetic polymers also have been considered to prevent adhesion formation. U.S. Pat. No. 5,605,938 to Roufa et al. describes methods and compositions for inhibiting cell invasion and fibrosis using dextran sulfate. The patent teaches that anionic polymers effectively inhibit invasion of cells associated with detrimental healing processes. The materials described, however, are not covalently polymerized, do not have mechanical integrity and do not bind to tissue. Such materials also may interfere with normal wound healing during the postoperative period.
Hydrogels are materials which absorb solvents (such as water), undergo rapid swelling without discernible dissolution, and maintain three-dimensional networks capable of reversible deformation. Because of their high water content and biocompatibility, hydrogels have been proposed for use as barriers for adhesion prevention.
U.S. Pat. No. 4,994,277 to Higham et al. describes the use of xanthan gum for preventing adhesions, wherein the hydrogel is more viscous than blood and is soluble in aqueous solutions. The water solubility of that gel system, however, enhances clearing and migration of the barrier. U.S. Pat. No. 4,911,926 to Henry et al. describes a method and composition for reducing post-surgical adhesions using aqueous and non-aqueous compositions comprising a polyoxyalkylene block copolymer. The resulting thermoreversible gels are not covalently crosslinked and have no mechanical integrity, thus making the barrier readily susceptible to displacement from the application site. The foregoing materials have shown limited efficacy in clinical trials.
U.S. Pat. No. 5,126,141 to Henry describes a composition and method for post-surgical adhesion reduction with thermo-irreversible gels of polyoxyalkylene polymers and ionic polysaccharides. These aqueous gels are rendered thermally irreversible upon contact with a counter-ion. A serious drawback of such systems is the biodegradability and absorbability of such barriers. Because there is no clear mechanism for the degradation of these ionically crosslinked materials, the barriers may remain biostable for uncertain periods of time and adversely impact the patient's health.
A similar disadvantage exists with respect to the barrier system described in U.S. Pat. No. 5,266,326 to Barry et al. That patent describes the in situ modification of alginate to form a hydrogel in vivo. Ionically crosslinked polysaccharides such as alginate are not absorbable in humans since no enzyme exists in humans to degrade the β glycosidic linkages. Moreover, the high molecular weight of the alginates used (upwards of 200,000 Da) do not allow filtration through the kidneys. The inability to eventually biodegrade the material is considered a major drawback.
U.S. Pat. No. 4,911,926 to Henry et al. describes aqueous and nonaqueous compositions comprised of block polyoxyalkylene copolymers that form gels in the biologic environment to prevent post-surgical adhesion. Other gel forming compositions have been suggested for use in preventing post-surgical adhesion, including: chitin derivatives (U.S. Pat. No. 5,093,319 to Henry et al.); chitosan-coagulum (U.S. Pat. No. 4,532,134 to Higham et al.); and hyaluronic acid (U.S. Pat. No. 4,141,973 to Balazs).
U.S. Pat. No. 4,886,787 to de Belder et al. describes a method of preventing adhesion between body tissues by employing a degradable gel of a crosslinked carboxyl-containing polysaccharide. U.S. Pat. No. 5,246,698 to Leshchiner et al. describes biocompatible viscoelastic gel slurries formed from a hyaluronan or a derivative thereof. The foregoing crosslinked gels are not formed in situ, but rather formed outside the body and then implanted as flowable gels. While covalent crosslinking of these materials may prolong residence time of the barrier within a body cavity, because the barriers are not formed in situ they do not adhere to the tissues within the body cavity and present a risk of migration.
Covalently crosslinked hydrogels (or aquagels) have been prepared based on crosslinked polymeric chains of methoxy poly(ethylene glycol) monomethacrylate having variable lengths of the polyoxyethylene side chains. Interaction of such hydrogels with blood components has been studied. See, e.g., Nagaoka, et al., in Polymers as Biomaterial (Shalaby et al., Eds.), Plenum Press, p. 381 (1983). A number of aqueous hydrogels have been used in various biomedical applications, such as, for example, soft contact lenses, wound management, and drug delivery. However, methods used in the preparation of these hydrogels, and conversion of these hydrogels to useful articles, are not suitable for forming these materials in situ in contact with living tissues.
U.S. Pat. No. 5,462,976 to Matsuda et al. describes photocurable glycosaminoglycan derivatives, crosslinked glycosaminoglycans and the use of such materials for tissue adhesion prevention. These materials, however, require external energy sources for transformation.
U.S. Pat. No. 5,410,016 to Hubbell et al. describes free radical polymerizable and biodegradable hydrogels that are formed from water soluble macromers. The patent describes the prevention of post-surgical adhesions using a local photopolymerization method, which shares the same disadvantage of requiring an external energy source. The patent also describes materials that are polymerizable by other free radical mechanisms, such as thermal or redox types of initiation.
Although these latter types of polymerization may be effectively exploited for the formation of regional barriers, only local methods for prevention of adhesion are taught in Hubbell et al. Also, effective concentrations used for the formation of local barriers using the aforementioned materials have been in the 10%–30% macromer concentration range, reflecting the structural integrity required to prevent migration of a locally adherent barrier. Such concentrations of hydrogel are unsuitable for regional barrier formation for several reasons, including:    1. The amount of macromer solution required for a regional barrier formation is in the range of 200 ml–3000 ml. At a 10–30% concentration the macromer would approach its toxicity limits for human use.    2. The structural integrity of the hydrogels formed at the foregoing concentrations may result in adverse effects similar to those seen from adhesions themselves, for example, due to the mobility restrictions that may result on visceral organs. Thus, formation of regional barriers at such concentrations may lead to postoperative pain and bowel obstructions.    3. Since such hydrogels have been observed to have an equilibrium water content in the range of 2–8%, the additional hydration of a large hydrogel mass in the abdominal or pelvic cavity may constrict and deform organs and tissue and thus have adverse effects. See, e.g., Sawhney et al., “Bioerodible hydrogels based on photopolymerized poly(ethylene glycol)-co-poly(α-hydroxy acid) diacrylate macromers”, Macromolecules, 26:581–587 (1993).
In view of the foregoing, it would be desirable to provide in situ formation of regional barriers by macromer solutions at concentrations close to the equilibrium hydration levels to reduce or prevent post-surgical adhesion formation.
It further would be desirable to provide methods that enable a surgeon to create a regional barrier with little reliance on skill and accuracy of placement, thereby overcoming some of the significant drawbacks of previously known local adhesion prevention barriers.